DESCRIPTION: Abuse of alcohol is a major social, economic and medical problem, accounting this year for 20-40% of hospitalizations, $167 billion in costs, and over 100,000 deaths according to the NIAAA (1999). The current very imperfect understanding of the physiological mechanisms involved in alcohol use and abuse is an important impediment to the development of effective therapies. Therefore, this application proposes a new direction in the analysis of the physiological control of alcohol ingestion in laboratory animals. That is to investigate the potential roles in alcohol intake of several peripheral and central regulatory peptides and of estradiol, all of which contribute to the regulation of food intake. The rationale of this proposal is that in addition to its central pharmacological effects, alcohol produces oropharyngeal, gastrointestinal and systemic stimuli similar to those occurring after food ingestion. Behavioral techniques that have been extremely useful in the investigation of the control of food intake will be applied to the analysis of the control of alcohol ingestion for the first time. These include the measurement of the microstructural organization of bouts of alcohol ingestion and the gastric sham feeding technique. Most work will be done in a genetic model of alcohol abuse, the Marchigian Sardinian alcohol-preferring (msP) rat. The msP rat prefers alcohol to water in a free-choice situation and chronically ingests intoxicating amounts of alcohol. In addition, we propose to investigate the control of alcohol intake in fa/fa and db/db mice that have mutations of the leptin receptor that lead to syndromes of hyperphagia and obesity. Finally, we propose to determine if any effects on alcohol ingestion in these mutant animals can be reversed by tissue-specific transgenic reinsertion of the normal gene. In order to increase the effectiveness and productivity of this program, work will proceed at two sites. The PI and his colleagues at the Bourne Behavioral Research Laboratory, Weill Medical College of Cornell University, have a long record of progress in the analysis of peripheral peptidergic mechanisms of the control of ingestion as well as the influence of estradiol on this control in females. The co-PI and his colleagues at the University of Camerino are experts in the analysis of alcohol ingestion and reward in alcohol-preferring rats, with special emphasis on central peptidergic controls of behavior. The work will be closely coordinated, and we expect this cooperative effort to be very productive.